Nitrogen-containing heterocyclic compound and method for producing same

ABSTRACT

There are provided a nitrogen-containing heterocyclic compound such as a substituted amino-pyridine-N-oxide compound represented by formula (1), which is useful as a synthetic intermediate for an agrochemical and the like; and a method for producing the nitrogen-containing heterocyclic compound. (In formula (1), R 1  and R 2  each represents a hydrogen atom or an unsubstituted or substituted alkyl group; R 3  represents a hydrogen atom, an unsubstituted or substituted alkylcarbonyl group or the like; R 4  represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group or the like; A represents a hydroxyl group, a thiol group or the like; m represents any one of integers of 1 to 4; k represents any one of integers of 0 to 3; and k+m≦4.)

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional application of U.S. application Ser.No. 13/638,700, filed on Oct. 1, 2012, which is a national phaseapplication of PCT/JP2011/057521 filed on Mar. 28, 2011, which claimspriority under 35 U.S.C. 119 to Japanese Patent Application No.2010-087915, filed Apr. 6, 2010, Japanese Patent Application No.2010-087916, filed Apr. 6, 2010, and Japanese Patent Application No.2010-107195, filed May 7, 2010, the contents of each are herebyincorporated by reference.

TECHNICAL FIELD

The present invention relates to a nitrogen-containing heterocycliccompound and a method for producing the same. More specifically, thepresent invention relates to: (1) a substituted amino-pyridine-N-oxidederivative which is useful as a synthetic intermediate of agriculturalchemicals or the like; (2) a method for producing a substitutedamino-6-methylpyridine-N-oxide derivative; and (3) a method forproducing a haloalkyl, nitrogen-containing heterocyclic derivative.

BACKGROUND ART

A 2-substituted amino-6-methylpyridine-N-oxide derivative is useful asan intermediate for the synthesis of chemical substances forpharmaceuticals and agrochemicals such as the tetrazolyloxime derivativedisclosed in Patent Document 1 since the halogenation or the like of amethyl group at position 6 is easy.

In general, pyridine-N-oxide derivatives can be obtained by theoxidation of pyridine derivatives. For example, in Patent Document 2, amethod for producing 2-chloro-pyridine-N-oxide by the oxidation of2-chloro-pyridine using hydrogen peroxide in the presence of a catalystrepresented by Y[PW₂O₁₃(OH)] (in which Y represents a hydrogen atom,alkyl or ammonium) has been disclosed.

In addition, with respect to the reaction of pyridine-N-oxidederivatives, as a method for introducing a halogen into the methyl groupof 2-picoline derivatives, for example, it has been reported inNon-Patent Document 1 that 6-chloro-2-chloromethyl pyridine can beproduced by rearranging 6-chloro-2-methylpyridine-N-oxide with aceticanhydride to introduce oxygen to the methyl group, followed by theaction of thionyl chloride thereon.

In Non-Patent Document 2, a halogenation method by reacting triphosgeneor diphosgene with 2-picoline-N-oxide in the presence ofdi-1-propylamine or triethylamine has been reported.

In addition, in Patent Document 3, a method to synthesize2-chloro-5-methylpyridine from 3-methylpyridine-1-oxide has been shown.According to Patent Document 3, it has been reported that a desiredproduct can be obtained by the method through a rearrangement reactionusing trimethylamine and phosgene to convert the 2nd position of thepyridine ring to trimethylammonium, followed by chlorination thereof.

CITATION LIST Patent Document

Patent Document 1: WO2008/006873

Patent Document 2: KR-A-10-2005-0025453

Patent Document 3: Japanese Unexamined Patent Application, FirstPublication No. Hei 7-252226

Patent Document 4: Japanese Unexamined Patent Application, FirstPublication No. Sho 62-142136

Non-Patent Document

Non-Patent Document 1: Barnes, J. H. et al., Tetrahedron 38 (22),3277-3280, 1982

Non-Patent Document 2: Narendar P. et al., Synthetic Communications 34(6), 1097-1103, 2004

SUMMARY OF INVENTION Technical Problem

The inventors of the present invention have an object of providing amethod for producing a substituted amino-pyridine-N-oxide derivativerepresented by the formula (1), in particular, a substitutedamino-6-alkyl-pyridine-N-oxide derivative, which is highly selective,easy to separate the catalyst, and also useful as an intermediate forthe synthesis of agricultural chemicals and the like. In addition,another object is to provide a highly selective and also high yieldmethod for producing a haloalkyl, nitrogen-containing heterocyclicderivative represented by the formula (5) which is also useful as anintermediate for the synthesis of pharmaceuticals and agrochemicals.

Solution to Problem

As a result of intensive and extensive studies in order to achieve theabove objects, the inventors of the present invention found that, amongthe tungstophosphoric acid salts represented by Q3 [PW₄O₂₄] that areknown as a catalyst for the epoxidation reaction in Patent Document 4 orthe like, by using those in which Q represents a quaternary nitrogencation as a catalyst, a substituted amino-6-methylpyridine-N-oxidederivative can be obtained with high selectivity through an oxidationreaction of a substituted amino-6-methylpyridine derivative with aperoxide, and that the catalyst can be easily separated after thecompletion of the reaction.

In addition, the inventors of the present invention have found that acompound represented by formula (5) can be produced in high yield andalso with high selectivity by reacting a compound represented by formula(4) with a halogenating agent such as thionyl chloride, thionyl bromideor sulfuryl chloride. Further, the inventors of the present inventionhave also discovered that a compound represented by formula (5) can beproduced in high yield and also with high selectivity by reacting acompound represented by formula (4) with a halogenating agent such asphosgene, diphosgene, triphosgene or phosphorus oxychloride in thepresence of a source of halogen ions which is soluble in an organicsolvent.

The present invention has been completed by further studies based onthese findings.

That is, the present invention includes the following aspects.

-   [1] A Substituted Amino-Pyridine-N-Oxide Compound Represented by    Formula (1):

(in the formula (1), each of R¹ and R² independently represents ahydrogen atom, or an unsubstituted or substituted alkyl group, and R¹and R² may form a ring together,

R³ represents a hydrogen atom, an unsubstituted or substitutedalkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group,or an unsubstituted or substituted alkoxycarbonyl group,

R⁴ represents an unsubstituted or substituted alkylcarbonyl group, anunsubstituted or substituted arylcarbonyl group, an unsubstituted orsubstituted heteroarylcarbonyl group, an unsubstituted or substitutedalkoxycarbonyl group, an unsubstituted or substituted alkylsulfonylgroup, or an unsubstituted or substituted arylsulfonyl group,

A represents a hydroxyl group, a thiol group, an amino group, a nitrogroup, a halogen atom or an organic group,

m represents any one of integers of 1 to 4, and

k represents any one of integers of 0 to 3,

wherein k+m≦4),

with the proviso that 2-ethoxycarbonylamino-6-methylpyridine-N-oxide isexcluded.

-   [2] A method for producing a substituted    amino-6-methylpyridine-N-oxide derivative represented by formula    (1-a) including oxidizing a substituted amino-6-methylpyridine    derivative represented by formula (2) using a peroxide in the    presence of a tungstophosphoric acid salt represented by formula    (3):

(in the formula,

A represents a hydroxyl group, a thiol group, an amino group, a nitrogroup, a halogen atom or an organic group,

k represents any one of integers of 0 to 3,

R³ represents a hydrogen atom, an unsubstituted or substitutedalkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group,or an unsubstituted or substituted alkoxycarbonyl group,

R⁴ represents an unsubstituted or substituted alkylcarbonyl group, anunsubstituted or substituted arylcarbonyl group, an unsubstituted orsubstituted heteroarylcarbonyl group, an unsubstituted or substitutedalkoxycarbonyl group, an unsubstituted or substituted alkylsulfonylgroup, or an unsubstituted or substituted arylsulfonyl group,

m represents any one of integers of 1 to 4,

wherein k+m≦4, and

Q represents a quaternary nitrogen cation).

-   [3] The method for producing a substituted    amino-6-methylpyridine-N-oxide derivative according to the above    aspect [2], wherein R³ in formula (2) and in formula (1-a) is a    hydrogen atom.-   [4] The method for producing a substituted    amino-6-methylpyridine-N-oxide derivative according to the above    aspect [2], wherein the quaternary nitrogen cation represented by Q    in formula (3) is a quaternary ammonium.-   [5] The method for producing a substituted    amino-6-methylpyridine-N-oxide derivative according to the above    aspect [2], wherein the tungstophosphoric acid salt represented by    formula (3) is obtained without an isolation operation after    preparation.-   [6] A method for producing a compound represented by formula (5)    including reacting a compound represented by formula (4) with a    halogenating agent:

(in the formula, each of a¹ to a⁴ independently represents a carbonatom, a nitrogen atom, an oxygen atom or a sulfur atom,

each of R¹ and R² independently represents a hydrogen atom, or anunsubstituted or substituted alkyl group, and R¹ and R² may form a ringtogether,

A represents a hydroxyl group, a thiol group, an amino group, a nitrogroup, a halogen atom or an organic group,

n represents any one of integers of 0 to 4, and a plurality of A may bebonded to form a ring when n is 2 or more, and

X represents a halogen atom).

-   [7] The method for producing a nitrogen-containing heterocyclic    compound according to the above aspect [6], wherein all of a¹ to a⁴    in formula (4) and formula (5) represent carbon atoms.-   [8] The method for producing a nitrogen-containing heterocyclic    compound according to the above aspect [6], wherein at least one of    A in formula (4) and formula (5) represents a group represented by    formula (6):

(in the formula (6), * indicates a binding site,

R⁵ represents a hydrogen atom, an unsubstituted or substitutedalkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group,an unsubstituted or substituted heteroarylcarbonyl group, anunsubstituted or substituted alkoxycarbonyl group, an unsubstituted orsubstituted alkylsulfonyl group, or an unsubstituted or substitutedarylsulfonyl group,

R⁶ represents an unsubstituted or substituted alkylcarbonyl group, anunsubstituted or substituted arylcarbonyl group, an unsubstituted orsubstituted 20 heteroarylcarbonyl group, an unsubstituted or substitutedalkoxycarbonyl group, an unsubstituted or substituted alkylsulfonylgroup, or an unsubstituted or substituted arylsulfonyl group, and R⁵ andR⁶ may be bonded to form a ring.)

-   [9] The method for producing a nitrogen-containing heterocyclic    compound according to the above aspect [6], wherein the compound    represented by formula (4) is a compound represented by formula (7),    and the compound represented by formula (5) is a compound    represented by formula (8):

(in the formula (7), A, R¹ and R² are the same as defined above,

1 represents any one of integers of 0 to 3,

R⁵ represents a hydrogen atom, an unsubstituted or substitutedalkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group,an unsubstituted or substituted heteroarylcarbonyl group, anunsubstituted or substituted alkoxycarbonyl group, an unsubstituted orsubstituted alkylsulfonyl group, or an unsubstituted or substitutedarylsulfonyl group,

R⁶ represents an unsubstituted or substituted alkylcarbonyl group, anunsubstituted or substituted arylcarbonyl group, an unsubstituted orsubstituted heteroarylcarbonyl group, an unsubstituted or substitutedalkoxycarbonyl group, an unsubstituted or substituted alkylsulfonylgroup, or an unsubstituted or substituted arylsulfonyl group, and R⁵ andR⁶ may be bonded to form a ring):

(in the formula (8), A, 1, R¹, R², X, R⁵ and R⁶ are the same as definedabove.)

-   [10] The method for producing a nitrogen-containing heterocyclic    compound according to the above aspect [8], wherein R⁵ represents an    unsubstituted or substituted alkylcarbonyl group, an unsubstituted    or substituted arylcarbonyl group, or an unsubstituted or    substituted alkoxycarbonyl group.-   [11] The method for producing a nitrogen-containing heterocyclic    compound according to the above aspect [6], wherein the halogenating    agent is at least one selected from the group consisting of thionyl    chloride, thionyl bromide and sulfuryl chloride.-   [12] The method for producing a nitrogen-containing heterocyclic    compound according to the above aspect [6], wherein the reaction is    carried out in the presence of a halogen ion source that is soluble    in an organic solvent.-   [13] The method for producing a nitrogen-containing heterocyclic    compound according to the above aspect [6], wherein the halogenating    agent is at least one selected from the group consisting of    phosgene, diphosgene, triphosgene and phosphorus oxychloride.-   [14] A method for producing a compound represented by formula (11)    including a step of converting a compound represented by formula (9)    into a compound represented by formula (10), and a step of reacting    the compound represented by formula (10) with a halogenating agent    to convert into the compound represented by formula (11):

(in the formula, each of R¹ and R² independently represents a hydrogenatom, or an unsubstituted or substituted alkyl group, and R¹ and R² mayform a ring together,

R⁶ represents an unsubstituted or substituted alkylcarbonyl group, anunsubstituted or substituted arylcarbonyl group, an unsubstituted orsubstituted heteroarylcarbonyl group, an unsubstituted or substitutedalkoxycarbonyl group, an unsubstituted or substituted alkylsulfonylgroup, or an unsubstituted or substituted arylsulfonyl group,

R⁷ represents an unsubstituted or substituted alkylcarbonyl group, anunsubstituted or substituted arylcarbonyl group, an unsubstituted orsubstituted heteroarylcarbonyl group, an unsubstituted or substitutedalkoxycarbonyl group, an unsubstituted or substituted alkylsulfonylgroup, or an unsubstituted or substituted arylsulfonyl group,

A represents a hydroxyl group, a thiol group, an amino group, a nitrogroup, a halogen atom or an organic group,

X represents a halogen atom,

m represents any one of integers of 1 to 4, and

k represents any one of integers of 0 to 3, wherein k+m<4.)

-   [15] The method for producing a nitrogen-containing heterocyclic    compound according to the above aspect [14], wherein a step of    synthesizing the compound represented by formula (11) is carried out    in the presence of a halogen ion source that is soluble in an    organic solvent.-   [16] A method for producing a compound represented by formula (13)    including reacting a compound represented by formula (9) with a    halogenating agent in the presence of a compound represented by    formula (12):

(in the formula, each of R¹ and R² independently represents a hydrogenatom, or an unsubstituted or substituted alkyl group, and R¹ and R² mayform a ring together,

R⁶ represents an unsubstituted or substituted alkylcarbonyl group, anunsubstituted or substituted arylcarbonyl group, an unsubstituted orsubstituted heteroarylcarbonyl group, an unsubstituted or substitutedalkoxycarbonyl group, an unsubstituted or substituted alkylsulfonylgroup, or an unsubstituted or substituted arylsulfonyl group,

R⁸ represents an unsubstituted or substituted alkylcarbonyl group, anunsubstituted or substituted arylcarbonyl group, or an unsubstituted orsubstituted alkoxycarbonyl group,

A represents a hydroxyl group, a thiol group, an amino group, a nitrogroup, a halogen atom or an organic group,

m represents any one of integers of 1 to 4,

k represents any one of integers of 0 to 3,

wherein k+m≦4,

X represents a halogen atom, and

X¹ represents a chlorine atom or a bromine atom).

-   [17] The method for producing a nitrogen-containing heterocyclic    compound according to the above aspect [16], wherein the reaction is    carried out in the presence of a halogen ion source that is soluble    in an organic solvent.-   [18] The production method according to the above aspect [12], [15]    or [17], wherein the halogen ion source that is soluble in an    organic solvent is a halogenated ammonium salt or a halogenated    phosphonium salt.-   [19] The production method according to the above aspect [12], [15]    or [17], wherein the halogen ion source that is soluble in an    organic solvent is a tertiary or quaternary alkyl ammonium halide    salt having an alkyl group of C₂ or more, or an alkyl phosphonium    halide salt having an alkyl group of C₂ or more.-   [20] The production method according to any one of the above aspects    [14] to [19], wherein the halogenating agent is at least one    selected from the group consisting of thionyl chloride, thionyl    bromide, phosphorus oxychloride, sulfuryl chloride, phosgene,    diphosgene and triphosgene.

Advantageous Effects of Invention

According to the production method of the present invention, asubstituted amino-pyridine-N-oxide derivative, a substitutedamino-6-methylpyridine-N-oxide derivative, and a haloalkyl,nitrogen-containing heterocyclic derivative can be obtained with highselectivity and also in high yield. The nitrogen-containing heterocycliccompound obtained by the production method of the present invention isuseful as an intermediate for the industrial production of agriculturalchemicals or the like.

DESCRIPTION OF EMBODIMENTS

[1] Substituted Amino-Pyridine-N-Oxide Derivative which is Useful asSynthetic Intermediate of Agricultural Chemicals or the Like

A substituted amino-pyridine-N-oxide derivative which is useful as asynthetic intermediate of agricultural chemicals or the like accordingto the present invention is a compound represented by the formula (1).

In the formula (1), each of R¹ and R² independently represents ahydrogen atom, or an unsubstituted or substituted alkyl group. R¹ and R²may be bonded to form a ring.

It should be noted that in the present invention, the term“unsubstituted” means that the corresponding group is composed only of acore group.

On the other hand, in the present invention, the term “substituted”means that any one of hydrogen atoms constituting the core group hasbeen substituted with a group having a different structure from that ofthe core group. Accordingly, the term “substituent” refers to anothergroup which substitutes the core group. The number of substituents maybe one or two or more. If two or more substituents are present, thesubstituents may be the same or may be different from each other.

Examples of the group which may serve as a “substituent” include a nitrogroup; a halogen atom such as a chlorine atom, a fluorine atom and abromine atom; a hydroxy group; an alkoxy group such as a methoxy group,an ethoxy group, an i-propoxy group, an n-propoxy group, an n-butoxygroup, an i-butoxy group, an s-butoxy group and a t-butoxy group; anaryloxy group such as a phenoxy group and a 1-naphthyloxy group; ahaloalkoxy group such as a fluoromethoxy group, a difluoromethoxy group,a trifluoromethoxy group, a 2-chloroethoxy group, a2,2,2-trichloroethoxy group, a 1,1,1,3,3,3-hexafluoro-2-propoxy group;an alkylthio group such as a methylthio group and an ethylthio group; anarylthio group such as a phenylthio group and a 1-naphthylthio group; analkyl group such as a methyl group and an ethyl group; an aryl groupsuch as a phenyl group and a naphthyl group; a heteroaryl group such asa pyrrolyl group, a thiazolyl group and a pyrimidinyl group; analkylcarbonyl group; an arylcarbonyl group; a heteroarylcarbonyl group;an alkoxycarbonyl group; an alkylsulfonyl group; and an arylsulfonylgroup.

Specific examples of the unsubstituted alkyl group for R¹ and R² includea methyl group, an ethyl group, an n-propyl group, an i-propyl group, ann-butyl group, an i-butyl group, an s-butyl group, a t-butyl group andan n-pentyl group, and C₁₋₆ alkyl groups are preferred.

Examples of the substituted alkyl group for R¹ and R² include acyanoalkyl group such as a cyanomethyl group, a 1-cyanoethyl group and a2-cyanoethyl group (cyano C₁₋₆ alkyl groups are preferred); a nitroalkylgroup such as a nitromethyl group (nitro C₁₋₆ alkyl groups arepreferred); a haloalkyl group such as a chloromethyl group, afluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a2-fluoroethyl group and a 2,2,2-trifluoroethyl group (halo C₁₋₆ alkylgroups are preferred); an alkoxyalkyl group such as a methoxymethylgroup, an ethoxymethyl group, a 1-methoxyethyl group and a2-methoxyethyl group (C₁₋₆ alkoxy C₁₋₆ alkyl groups are preferred); anarylalkyl group such as a phenylmethyl group and a 1-naphthylethyl group(C₆₋₁₀ aryl C₁₋₆ alkyl groups are preferred); and a heteroarylalkylgroup such as 2-pyridylmethyl group (5-6 membered heteroaryl C₁₋₆ alkylgroups are preferred).

Examples of the ring to be formed by the bonding of R¹ and R² include acycloalkyl group such as a cyclopropyl group and a cyclobutyl group(C₃₋₈ cycloalkyl groups are preferred); a cycloalkenyl group such as acyclohexenyl group (C₃₋₈ cycloalkenyl groups are preferred); and asaturated heterocyclic group such as a morpholino group (3 to 8-memberedsaturated heterocyclic groups are preferred).

In the formula (1), R³ represents a hydrogen atom, an unsubstituted orsubstituted alkylcarbonyl group, an unsubstituted or substitutedarylcarbonyl group, or an unsubstituted or substituted alkoxycarbonylgroup.

Examples of the unsubstituted alkylcarbonyl group for R³ include an acylgroup and an ethylcarbonyl group, and C₁₋₆ alkylcarbonyl groups arepreferred.

Examples of the substituted alkylcarbonyl group for R³ include a cyanoalkylcarbonyl group such as a cyano methylcarbonyl group (cyano C₁₋₆alkyl carbonyl groups are preferred); a nitro alkyl carbonyl group suchas a 1-nitro ethyl carbonyl group (nitro C₁₋₆ alkyl carbonyl groups arepreferred); a haloalkylcarbonyl group such as a chloromethyl carbonylgroup, a difluoromethyl carbonyl group and a 2,2,2-trifluoroethylcarbonyl group (halo C₁₋₆ alkyl carbonyl groups are preferred); analkoxy alkyl carbonyl group such as a methoxy acyl group and a2-methoxyethyl carbonyl group (C₁₋₆ alkoxy C₁₋₆ alkyl carbonyl groupsare preferred); an aryl alkyl carbonyl group such as a phenyl methylcarbonyl group and a 1-naphthyl ethyl carbonyl group (C₆₋₁₀ aryl C₁₋₆alkyl carbonyl groups are preferred); and a heteroaryl alkyl carbonylgroup such as a 2-pyridyl methyl carbonyl group (5-6 membered heteroarylC₁₋₆ alkyl carbonyl groups are preferred).

Examples of the unsubstituted arylcarbonyl group for R³ include abenzoyl group and a 2-naphthyl carbonyl group, and C₆₋₁₀ arylcarbonylgroups are preferred.

Examples of the substituted arylcarbonyl group for R³ include anarylcarbonyl group substituted with a nitro group, such as a 4-nitrophenyl carbonyl group (C₆₋₁₀ arylcarbonyl groups substituted with anitro group are preferred); an arylcarbonyl group substituted with acyano group such as a 2-cyanophenyl carbonyl group (C₆₋₁₀ arylcarbonylgroups substituted with a cyano group are preferred); an arylcarbonylgroup substituted with an alkyl group such as a 2-methyl phenyl carbonylgroup and a 3,5-dimethylphenyl carbonyl group (C₆₋₁₀ arylcarbonyl groupssubstituted with a C₁₋₆ alkyl group are preferred); and an arylcarbonylgroup substituted with a halogen atom such as a 4-chlorophenyl carbonylgroup and a 3,5-difluorophenyl carbonyl group (C₆₋₁₀ arylcarbonyl groupssubstituted with a halogen atom are preferred).

Examples of the unsubstituted alkoxycarbonyl group for R³ include amethoxycarbonyl group and an ethoxycarbonyl group, and C₁₋₆alkoxycarbonyl groups are preferred.

Examples of the substituted alkoxycarbonyl group for R³ include a cyanoalkoxycarbonyl group such as a cyano methoxycarbonyl group (cyano C₁₋₆alkoxycarbonyl groups are preferred); a nitro alkoxycarbonyl group suchas a 1-nitro ethoxycarbonyl group (nitro C₁₋₆ alkoxycarbonyl groups arepreferred); a haloalkoxycarbonyl group such as a chloromethoxy carbonylgroup, a difluoromethoxy carbonyl group and a 2,2,2-trifluoroethoxycarbonyl group (halo C₁₋₆ alkoxycarbonyl groups are preferred); analkoxy alkoxycarbonyl group such as a methoxy methoxy carbonyl group anda 2-methoxyethoxy carbonyl group (C₁₋₆ alkoxy C₁₋₆ alkoxy carbonylgroups are preferred); an aryl alkoxycarbonyl group such as a phenylmethoxy carbonyl group and a 1-naphthyl ethoxy carbonyl group (C₆₋₁₀aryl C₁₋₆ alkoxycarbonyl groups are preferred); and a heteroaryl alkoxygroup such as a 2-pyridyl methoxy carbonyl group (5-6 memberedheteroaryl C₁₋₆ alkoxycarbonyl groups are preferred).

In the formula (1), R⁴ represents an unsubstituted or substitutedalkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group,an unsubstituted or substituted heteroarylcarbonyl group, anunsubstituted or substituted alkoxycarbonyl group, an unsubstituted orsubstituted alkylsulfonyl group, or an unsubstituted or substitutedarylsulfonyl group.

Specific examples of the unsubstituted or substituted alkylcarbonylgroup, the unsubstituted or substituted arylcarbonyl group, and theunsubstituted or substituted alkoxycarbonyl group for R⁴ include thesame as those described above as specific examples for R³.

The heteroaryl carbonyl group for R⁴ is one in which a monocyclicheteroaryl ring or fused heteroaryl ring containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogenatom and a sulfur atom is bonded to a carbonyl group, and a 5- to6-membered heteroaryl carbonyl group is preferred.

Examples of the unsubstituted heteroaryl carbonyl group for R⁴ include apyrrolyl carbonyl group, a furyl carbonyl group, a thienyl carbonylgroup, an imidazolyl carbonyl group, a pyrazolyl carbonyl group, athiazolyl carbonyl group, an isothiazolyl carbonyl group, an oxazolylcarbonyl group, an isooxazolyl carbonyl group, a triazolyl carbonylgroup, a tetrazolyl carbonyl group, an oxadiazolyl carbonyl group, a1,2,3-thiadiazolyl carbonyl group, a 1,2,4-thiadiazolyl carbonyl group,a 1,3,4-thiadiazolyl carbonyl group, a pyridyl carbonyl group, apyrazinyl carboxy group, a pyrimidinyl carbonyl group, a pyridazinylcarboxyl group, a 1,2,4-triazinyl carbonyl group, a 1,3,5-triazinylcarbonyl group, an indolyl carbonyl group, a benzofuranylcarbonyl group,a benzothienylcarbonyl group, a benzimidazolylcarbonyl group, abenzopyrazolylcarbonyl group, a benzooxazolylcarbonyl group, abenzoisooxazolylcarbonyl group, a benzothiazolylcarbonyl group, abenzoisothiazolylcarbonyl group, an indazolylcarbonyl group, apurinylcarbonyl group, a quinolylcarbonyl group, an isoquinolylcarbonylgroup, a phthalazinylcarbonyl group, a naphthyridinylcarbonyl group, aquinoxalinylcarbonyl group, a quinazolinylcarbonyl group, acinnolinylcarbonyl group, a pteridinylcarbonyl group and apyrido[3,2-b]pyridylcarbonyl group.

Examples of the substituted heteroaryl carbonyl group for R⁴ include aheteroaryl carbonyl group substituted with a cyano group such as a3-cyano-2-pyridylcarbonyl group; a heteroaryl carbonyl group substitutedwith a nitro group such as a 4-nitro-2-pyridylcarbonyl group; aheteroaryl carbonyl group substituted with a halogen atom such as a5-fluoro-2-pyridylcarbonyl group; a heteroaryl carbonyl groupsubstituted with an alkyl group such as a 6-methyl-2-pyridylcarbonylgroup (C₁₋₆ alkyl 5-6 membered heteroaryl carbonyl groups arepreferred); a heteroaryl carbonyl group substituted with an alkoxy groupsuch as a 2-methoxy-3-pyridylcarbonyl group (C₁₋₆ alkoxy 5-6 memberedheteroaryl carbonyl groups are preferred); a heteroaryl carbonyl groupsubstituted with an aryl group such as a 4-phenyl-3-pyridylcarbonylgroup (C₆₋₁₀ aryl 5-6 membered heteroaryl carbonyl groups arepreferred); and a heteroaryl carbonyl group substituted with aheteroaryl group such as a 5-(2-pyridyl)-3-pyridylcarbonyl group (5-6membered heteroaryl 5-6 membered heteroaryl carbonyl groups arepreferred).

Examples of the unsubstituted alkylsulfonyl group for R⁴ include amethylsulfonyl group and an ethylsulfonyl group, and C₁₋₆ alkylsulfonylgroups are preferred.

Examples of the substituted alkylsulfonyl group for R⁴ include a cyanoalkylsulfonyl group such as a cyano methylsulfonyl group (cyano C₁₋₆alkylsulfonyl groups are preferred); a nitro alkylsulfonyl group such asa 1-nitro ethylsulfonyl group (nitro C₁₋₆ alkylsulfonyl groups arepreferred); a haloalkylsulfonyl group such as a chloromethyl sulfonylgroup, a difluoromethyl sulfonyl group and a 2,2,2-trifluoroethylsulfonyl group (halo C₁₋₆ alkylsulfonyl groups are preferred); an alkoxyalkylsulfonyl group such as a methoxy methylsulfonyl group and a2-methoxy ethylsulfonyl group (C₁₋₆ alkoxy C₁₋₆ alkylsulfonyl groups arepreferred); an aryl alkylsulfonyl group such as a phenyl methylsulfonylgroup and a 1-naphthyl ethyl sulfonyl group (C₆₋₁₀ aryl C₁₋₆alkylsulfonyl groups are preferred); and a heteroaryl alkylsulfonylgroup such as a 2-pyridyl methylsulfonyl group (5-6 membered heteroarylC₁₋₆ alkylsulfonyl groups are preferred).

Examples of the unsubstituted arylsulfonyl group for R⁴ include aphenylsulfonyl group and a 2-naphthylsulfonyl group, and C₆₋₁₀arylsulfonyl groups are preferred.

Examples of the substituted arylsulfonyl group for R⁴ include anarylsulfonyl group substituted with a cyano group such as a 2-cyanophenylsulfonyl group (C₆₋₁₀ arylsulfonyl groups substituted with a cyanogroup are preferred); an arylsulfonyl group substituted with a nitrogroup such as a 4-nitrophenylsulfonyl group (C₆₋₁₀ arylsulfonyl groupssubstituted with a nitro group are preferred); an arylsulfonyl groupsubstituted with a halogen atom such as a 4-chlorophenylsulfonyl groupand a 3,5-difluorophenylsulfonyl group (C₆₋₁₀ arylsulfonyl groupssubstituted with a halogen atom are preferred); an arylsulfonyl groupsubstituted with an alkyl group such as a 2-methylphenylsulfonyl groupand a 3,5-dimethyl phenylsulfonyl group (C₆₋₁₀ arylsulfonyl groupssubstituted with a C₁₋₆ alkyl group are preferred); and an arylsulfonylgroup substituted with an alkoxy group such as a 4-methoxyphenylsulfonylgroup (C₆₋₁₁) arylsulfonyl groups substituted with a C₁₋₆ alkoxy groupare preferred).

In the formula (1), A represents a hydroxyl group, a thiol group, anamino group, a nitro group, a halogen atom or an organic group.

Examples of the halogen atom for A include a fluorine atom, a chlorineatom, a bromine atom and an iodine atom.

The organic group for A is a general description that represents allgroups containing a carbon atom within a substituent, and examplesthereof include a cyano group, an amino group having a substituent(amino groups substituted with a C₁₋₆ alkyl group or a C₆₋₁₀ aryl groupare preferred); an unsubstituted or substituted alkyl group (C₁₋₆alkylgroups substituted with a nitro group, a halogen atom, a C₁₋₆ alkoxygroup or a C₆₋₁₀ aryl group are preferred), an unsubstituted orsubstituted alkenyl group (C₂₋₆ alkenyl groups substituted with a nitrogroup, a halogen atom, a C₁₋₆ alkoxy group or a C₆₋₁₀ aryl group arepreferred), an unsubstituted or substituted alkynyl group (C₂₋₆ alkynylgroups substituted with a nitro group, a halogen atom, a C₁₋₆ alkoxygroup or a C₆₋₁₀ aryl group are preferred), an unsubstituted orsubstituted aryl group (C₆₋₁₀ aryl groups substituted with a nitrogroup, a halogen atom, a C₁₋₆ alkyl group or a halo C₁₋₆ alkyl group arepreferred), an unsubstituted or substituted heteroaryl group (5-6membered heteroaryl groups substituted with a nitro group, a halogenatom, a C₁₋₆ alkyl group or a halo C₁₋₆ alkyl group are preferred), anunsubstituted or substituted alkoxy group (C₁₋₆ alkoxy groupssubstituted with a nitro group, a halogen atom, a C1-6 alkoxy group or aC₆₋₁₀ aryl group are preferred), an unsubstituted or substitutedalkenyloxy group (C₂₋₆ alkenyloxy groups substituted with a nitro group,a halogen atom, a C₁₋₆ alkoxy group or a C₆₋₁₀ aryl group arepreferred), an unsubstituted or substituted alkynyloxy group (C₂₋₆alkynyloxy groups substituted with a nitro group, a halogen atom, a C₁₋₆alkoxy group or a C₆₋₁₀ aryl group are preferred), an unsubstituted orsubstituted aryloxy group (C₆₋₁₀ aryloxy groups substituted with a nitrogroup, a halogen atom, a C₁₋₆ alkyl group or a halo C₁₋₆ alkyl group arepreferred), an unsubstituted or substituted heteroaryloxy group (5-6membered heteroaryloxy groups substituted with a nitro group, a halogenatom, a C₁₋₆ alkyl group or a halo C₁₋₆ alkyl group are preferred), aformyl group, an unsubstituted or substituted alkylcarbonyl group (C₁₋₆alkylcarbonyl groups substituted with a nitro group, a halogen atom, aC₁₋₆ alkoxy group or a C₆₋₁₀ aryl group are preferred), an unsubstitutedor substituted alkenylcarbonyl group (C₂₋₆ alkenylcarbonyl groupssubstituted with a nitro group, a halogen atom, a C₁₋₆ alkoxy group or aC₆₋₁₀ aryl group are preferred), an unsubstituted or substitutedalkynylcarbonyl group (C₂₋₆ alkynylcarbonyl groups substituted with anitro group, a halogen atom, a C₁₋₆ alkoxy group or a C₆₋₁₀ aryl groupare preferred), an unsubstituted or substituted arylcarbonyl group(C₆₋₁₀ arylcarbonyl groups substituted with a nitro group, a halogenatom, a C₁₋₆ alkyl group or a halo C₁₋₆ alkyl group are preferred), anunsubstituted or substituted heteroarylcarbonyl group (5-6 memberedheteroarylcarbonyl groups substituted with a nitro group, a halogenatom, a C₁₋₆ alkyl group or a halo C₁₋₆ alkyl group are preferred), anunsubstituted or substituted alkylthio group (C₁₋₆ alkylthio groupssubstituted with a nitro group, a halogen atom, a C₁₋₆ alkoxy group or aC₆₋₁₀ aryl group are preferred), an unsubstituted or substitutedalkenylthio group (C₂₋₆ alkenylthio groups substituted with a nitrogroup, a halogen atom, a C₁₋₆ alkoxy group or a C₆₋₁₀ aryl group arepreferred), an unsubstituted or substituted alkynylthio group (C₂₋₆alkynylthio groups substituted with a nitro group, a halogen atom, aC₁₋₆ alkoxy group or a C₆₋₁₀ aryl group are preferred), an unsubstitutedor substituted arylthio group (C₆₋₁₀ arylthio groups substituted with anitro group, a halogen atom, a C₁₋₆ alkyl group or a halo C₁₋₆ alkylgroup are preferred), an unsubstituted or substituted heteroarylthiogroup (5-6 membered heteroarylthio groups substituted with a nitrogroup, a halogen atom, a C₁₋₆ alkyl group or a halo C₁₋₆ alkyl group arepreferred), an unsubstituted or substituted alkylsulfinyl group (C₁₋₆alkylsulfinyl groups substituted with a nitro group, a halogen atom, aC₁₋₆ alkoxy group or a C₆₋₁₀ aryl group are preferred), an unsubstitutedor substituted alkenylsulfinyl group (C₂₋₆ alkenylsulfinyl groupssubstituted with a nitro group, a halogen atom, a C₁₋₆ alkoxy group or aC₆₋₁₀ aryl group are preferred), an unsubstituted or substitutedalkynylsulfinyl group (C₂₋₆ alkynylsulfinyl groups substituted with anitro group, a halogen atom, a C₁₋₆ alkoxy group or a C₆₋₁₀ aryl groupare preferred), an unsubstituted or substituted arylsulfinyl group(C₆₋₁₀ arylsulfinyl groups substituted with a nitro group, a halogenatom, a C₁₋₆ alkyl group or a halo C₁₋₆ alkyl group are preferred), anunsubstituted or substituted heteroarylsulfinyl group (5-6 memberedheteroarylsulfinyl groups substituted with a nitro group, a halogenatom, a C₁₋₆ alkyl group or a halo C₁₋₆ alkyl group are preferred), anunsubstituted or substituted alkylsulfonyl group (C₁₋₆ alkylsulfonylgroups substituted with a nitro group, a halogen atom, a C₁₋₆ alkoxygroup or a C₆₋₁₀ aryl group are preferred), an unsubstituted orsubstituted alkenylsulfonyl group (C₂₋₆ alkenylsulfonyl groupssubstituted with a nitro group, a halogen atom, a C₁₋₆ alkoxy group or aC₆₋₁₀ aryl group are preferred), an unsubstituted or substitutedalkynylsulfonyl group (C₂₋₆ alkynylsulfonyl groups substituted with anitro group, a halogen atom, a C₁₋₆ alkoxy group or a C₆₋₁₀ aryl groupare preferred), an unsubstituted or substituted arylsulfonyl group(C₆₋₁₀ arylsulfonyl groups substituted with a nitro group, a halogenatom, a C₁₋₆ alkyl group or a halo C₁₋₆ alkyl group are preferred), andan unsubstituted or substituted heteroarylsulfonyl group (5-6 memberedheteroarylsulfonyl groups substituted with a nitro group, a halogenatom, a C₁₋₆ alkyl group or a halo C₁₋₆ alkyl group are preferred).

In the formula (1), m represents any one of integers of 1 to 4, and ispreferably 1.

In the formula (1), k represents any one of integers of 0 to 3.

In addition, k+m≦4, with the proviso that2-ethoxycarbonylamino-6-methylpyridine-N-oxide is excluded in theformula (1).

[2] Method for Producing Substituted Amino-6-Methylpyridine-N-OxideDerivative

The production method of the present invention includes oxidation of asubstituted amino-6-methylpyridine derivative represented by formula (2)using a peroxide in the presence of a tungstophosphoric acid saltrepresented by formula (3). By the production method of the presentinvention, it is possible to obtain a substitutedamino-6-methylpyridine-N-oxide derivative represented by formula (1-a).

The substituted amino-6-methylpyridine derivative used in the productionmethod of the present invention is a compound represented by formula(2).

Specific examples of A, R³ and R⁴ in formula (2) or formula (1-a)include the same as those described above as specific examples in theaforementioned formula (1). m and k in formula (2) or formula (1-a) arethe same as defined above as m and k in the aforementioned formula (1).

Among these, R³ is preferably an unsubstituted or substitutedalkoxycarbonyl group, more preferably an unsubstituted or substitutedC₁₋₆ alkoxycarbonyl group, and still more preferably a t-butoxy group.

Among these, R⁴ is preferably a hydrogen atom, or an unsubstituted orsubstituted arylcarbonyl group, more preferably a hydrogen atom or abenzoyl group, and still more preferably a hydrogen atom.

As a substitution position for NR³R⁴, the 2nd position of pyridine ispreferred.

The substituted amino-6-methylpyridine derivative represented by theformula (2) can be obtained, for example, by reacting an acid chlorideor acid anhydride with commercially available 2-amino-6-methylpyridinein the presence of a base such as pyridine or triethylamine Morespecifically, it is possible to obtain2-[(t-butoxycarbonyl)amino]-6-methylpyridine by using di-t-butyldicarbonate in the reaction as the acid anhydride.

The tungstophosphoric acid salt used in the production method of thepresent invention is a compound represented by formula (3).

[PW₄O₂₄] in formula (3) is a peroxotungsten heteropolyanion. The anionmay also be represented by the formula {PO₄[W(O)(O₂)₂]₄}.

Q in the formula (3) represents a quaternary nitrogen cation.

As a quaternary nitrogen cation, there are quaternary ammonium, iminium,diazonium, cations of non-cyclic nitrogen skeletons, cations ofnitrogen-containing cyclic skeletons, and the like.

Examples of the quaternary ammonium include tetramethylammonium,tetraethylammonium, tetra-(n-butyl)ammonium, tetraphenylammonium,tetrabenzylammonium, N,N,N-trimethylbenzylammonium,N,N,N-tri(n-butyl)benzylammonium, hexadecyltrimethylammonium,dihexadecyl dimethylammonium, trioctadecylmethylammonium,dioctadecyldimethylammonium, trioctylmethylammonium,N,N,N-trimethylanilinium andN,N,N,N′,N′,N′-hexamethylethane-1,2-diaminium.

Examples of the iminium include benzylidene-t-butylmethylammonium anddibenzhydrylidene ammonium.

Examples of the diazonium include benzene diazonium,naphthalene-2-diazonium and benzene-1,4-bis(diazonium).

Examples of the cations of non-cyclic nitrogen skeletons include1,1-dimethyl-1-phenyldiazan-1-ium, hexamethyldiazan-1,2-dium,2,2-dimethyltriazan-2-ium, 1,2-dimethyltriazan-1-ium,1,1,1,3-tetramethyltriaza-2-en-1-ium and1H-4λ⁵-pyrido[1,2,3-de]quinoxalin-4-ylium.

Examples of the cations of nitrogen-containing cyclic skeletons include2,2-diethyl-2,5-diazabicyclo[4.2.2]decan-2-ium,1,3-dimethylpyridin-1-ium, 3,7-dibromo-5-methylphenazin-5-ium,1,3-dimethyl-1H-benzimidazol-3-ium,1,1,4,4-tetramethylpiperazin-1,4-dium and cetyl pyridinium.

Among these, from the viewpoints of selectivity and reactivity, Q ispreferably a quaternary ammonium, more preferably tetra-(n-butyl)ammonium or benzyltri(n-butyl)ammonium, and particularly preferablytetra-(n-butyl) ammonium.

The tungstophosphoric acid salt represented by the formula (3) can beobtained by the method described in Patent Document 4 or the like. Forexample, by dissolving sodium tungstate (VI) in distilled water, addingan aqueous solution of phosphoric acid to the obtained solution, andthen adding concentrated sulfuric acid to adjust the pH to an acidicrange, followed by addition of hydrogen peroxide, stirring at roomtemperature, and then, adding a halogenated quaternary ammonium such astetra-(n-butyl)ammonium chloride, it is possible to obtain thetungstophosphoric acid salt represented by the formula (3) such astri[tetra-(n-butyl)ammonium]tetra(diperoxotungsto)phosphoric acid salt.

The tungstophosphoric acid salt represented by the formula (3) which isused in the production method of the present invention can be isolatedand purified after preparation to be subjected to an oxidation reaction,although it can also be subjected to an oxidation reaction continuouslywithout carrying out an isolation operation. From the viewpoint of easeof operation, the prepared tungstophosphoric acid salt which isrepresented by the formula (3) is preferably subjected to an oxidationreaction continuously without carrying out an isolation operation. Itshould be noted that the isolation operation includes filtration,washing, and the like.

The used amount of tungstophosphoric acid salt represented by theformula (3) is not particularly limited, although it is preferably 0.001mol % to 1,000 mol %, more preferably 0.01 mol % to 100 mol %, andparticularly preferably 0.1 mol % to 10 mol %, relative to thesubstituted amino-6-methylpyridine derivative represented by the formula(2).

The peroxide used in the oxidation reaction in the production method ofthe present invention is not particularly limited. Examples thereofinclude organic peroxides such as dicumyl peroxide,1,1-di-t-butylperoxy-3,3,5-trimethylcyclohexane, 1,1-di-t-butylperoxycyclohexane, 2,2-di-t-butyl peroxybutane, n-butyl 4,4-t-butylperoxyvalerate, 2,2-bis(4,4-di-t-butylperoxycyclohexane)propane,2,2,4-trimethylpentyl peroxyneodecanoate, α-cumyl peroxyneodecanoate,t-butyl peroxyneohexanoate, t-butyl peroxyacetate, t-butylperoxylaurate, t-butyl peroxybenzoate, t-butyl peroxyisophthalate,peracetic acid and performic acid; and inorganic peroxides such ashydrogen peroxide and sodium peroxide.

Of these, hydrogen peroxide is preferred from the viewpoints of safety,economy and selectivity.

The used amount of peroxide is not particularly limited, although it ispreferably 100 mol % to 2,000 mol %, more preferably 100 mol % to 1,000mol %, and particularly preferably 100 mol % to 200 mol %, relative tothe substituted amino-6-methylpyridine derivative represented by theformula (2).

In addition, an aqueous hydrogen peroxide solution may be used as theperoxide. The concentration of the aqueous hydrogen peroxide solution isnot particularly limited, although it is preferably 0.1 to 70% byweight, more preferably 5 to 40% by weight, and particularly preferably30 to 35% by weight.

In the production method of the present invention, the reaction may becarried out in the presence of an organic solvent. The organic solventis not particularly limited as long as it is an organic solvent capableof dissolving the substituted amino-6-methylpyridine derivativerepresented by the formula (2) without being oxidized. Examples thereofinclude acetonitrile, benzene, acetone, methylene chloride, chloroformand dioxane. For example, when using hydrogen peroxide as the peroxide,as a solvent, methylene chloride or chloroform is preferred, andchloroform is particularly preferred.

The temperature from the start of the oxidation reaction until the endof the oxidation reaction is not particularly limited, although thetemperature is preferably from −78° C. to 200° C., more preferably from−20° C. to 120° C., and particularly preferably from 10° C. to 100° C.When the temperature is too high, side reactions tend to proceed. Whenthe temperature is too low, the reactions tend to proceed poorly. Thetime for the oxidation reaction may be appropriately selected dependingon the scale of the reaction. The progress of the reaction may beobserved, for example, by general analysis, such as gas chromatography,high-performance liquid chromatography, thin layer chromatography, NMRor IR.

By the oxidation reaction as described above, it is possible to obtain asubstituted amino-6-methylpyridine-N-oxide derivative represented byformula (1-a). After completion of the oxidation reaction, thesubstituted amino-6-methylpyridine-N-oxide derivative represented byformula (1-a) which has been generated may be isolated. The isolationmethod may be appropriately selected in accordance with the type ofperoxide used in the oxidation reaction or the nature of the targetproduct. For example, when hydrogen peroxide is used as the peroxide,after the completion of the oxidation reaction or after decomposing theremaining hydrogen peroxide with a reducing agent such as sodiumsulfite, water and an organic solvent, if necessary, are added to thereaction solution, followed by performing an extraction and liquidseparation operation, and then concentrating the separated organic layerto isolate a desired product.

In addition, an aqueous layer obtained by the liquid separationoperation contains a tungstophosphoric acid salt represented by formula(3), and therefore the aqueous layer may be reused as it is or afterconducting a concentration treatment or the like as needed for theoxidation reaction in the production method of the present invention.

The production method of the present invention is economical because theremoval of tungstophosphoric acid salt represented by the formula (3)after the reaction is easy, and the reuse thereof is also possible.

In addition, the substituted amino-6-methylpyridine-N-oxide derivativerepresented by formula (1-a) which is obtained by the production methodof the present invention is useful as an intermediate in the manufactureof agricultural chemicals or the like.

[3] Method for Producing Haloalkyl-Nitrogen-Containing HeterocyclicDerivative

[3-1] First Embodiment

The method for producing a haloalkyl nitrogen-containing heterocycliccompound according to the present invention includes a step of reactinga compound represented by formula (4) with a halogenating agent tosynthesize a compound represented by formula (5).

The raw material used in the production method of the present inventionis a compound represented by formula (4).

In the formula (4), each of a¹, a², a³ and a⁴ independently represents acarbon atom, a nitrogen atom, an oxygen atom or a sulfur atom. Of thepossibilities, it is preferable that all of a¹, a², a³ and a⁴ representa carbon atom.

Specific examples of R¹, R² and A in formula (4) include the same asthose described above as specific examples in the aforementioned formula(1).

n indicates the number of substitutents of A, and is any one of integersof 0 to 4. When n is 2 or more, each A may be the same or may bedifferent from each other.

In addition, more than one A may be bonded with each other to form aring, such as a quinoline ring, an isoquinoline ring, a2,6-naphthyridine ring, a 1,8-naphthyridine ring, a phthalazine ring, aquinoxaline ring, a quinazoline ring, a pteridine ring, or a purinering.

In the present invention, at least one of A is preferably a grouprepresented by formula (6).

In the formula (6), * indicates a binding site.

In the formula (6), R⁵ represents a hydrogen atom, an unsubstituted orsubstituted alkylcarbonyl group, an unsubstituted or substitutedarylcarbonyl group, an unsubstituted or substituted heteroarylcarbonylgroup, an unsubstituted or substituted alkoxycarbonyl group, anunsubstituted or substituted alkylsulfonyl group, or an unsubstituted orsubstituted arylsulfonyl group, and specific examples thereof includethe same as those described above as specific examples for R⁴ in theaforementioned formula (1). Of these, an unsubstituted or substitutedalkylcarbonyl group (more preferably, an unsubstituted or substitutedC₁₋₆ alkylcarbonyl group), an unsubstituted or substituted arylcarbonylgroup (more preferably, an unsubstituted or substituted C₆₋₁₀arylcarbonyl group), or an unsubstituted or substituted alkoxycarbonylgroup (more preferably, an unsubstituted or substituted C₁₋₆alkoxycarbonyl group) is preferable.

In the formula (6), R⁶ represents an unsubstituted or substitutedalkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group,an unsubstituted or substituted heteroarylcarbonyl group, anunsubstituted or substituted alkoxycarbonyl group, an unsubstituted orsubstituted alkylsulfonyl group, or an unsubstituted or substitutedarylsulfonyl group, and specific examples thereof include the same asthose described above as specific examples for R⁴ in the aforementionedformula (1).

R⁵ and R⁶ may be bonded to form a ring.

In the production method of the present invention, among the compoundsrepresented by formula (4) that are raw materials, a compoundrepresented by formula (7) is preferably used.

In the formula (7), A, R¹, R², R⁵ and R⁶ are the same as A, R¹, R², R⁵and R⁶ defined above in formula (4) and formula (6).

In the formula (7), 1 indicates the number of substituents of A, and isany one of integers from 0 to 3. When 1 is 2 or more, each A may be thesame or may be different from each other, and may also be bonded witheach other to form a ring.

The compounds represented by the formula (4) or formula (7) may beobtained by oxidizing the corresponding 2-picoline derivative using aknown method, for example, an oxidation method usingmeta-chloroperbenzoic acid, an oxidation method using hydrogen peroxidein the presence of tungstic acid (refer to U.S. Pat. No. 3,047,579), orthe like.

(Halogenating Agent)

The halogenating agent used in the present invention is not particularlylimited as long as it is an agent used for halogenation in a knownsynthesis reaction.

Examples of the halogenating agent include thionyl chloride, thionylbromide, sulfuryl chloride, phosgene, diphosgene, triphosgene andphosphorus oxychloride.

Among these, thionyl chloride, thionyl bromide or sulfuryl chloride iscapable of suppressing the generation of byproducts and increasing theselectivity and yield for the synthesis reaction of the compoundrepresented by formula (4), even without the presence of a halogen ionsource described later.

In addition, phosgene, diphosgene, triphosgene or phosphorus oxychlorideallows the reaction to proceed under mild conditions and also increasesthe selectivity and yield for the synthesis reaction of the compoundrepresented by formula (4). Phosgene, diphosgene, triphosgene orphosphorus oxychloride may be suitably used when R⁵ in the formula (6)represents a hydrogen atom.

The amount of the halogenating agent used is not particularly limited,although it is preferably from 0.8 to 10 equivalent, and more preferablyfrom 1.5 to 2.5 equivalents, relative to the compound represented byformula (4). However, for diphosgene and triphosgene, it is preferableto convert each of the equivalent values described above for phosgenefor use.

(Halogen Ion Source)

The halogen ion source soluble in organic solvents which is used in thepresent invention is a salt containing a halogen anion which is solublein organic solvents.

Examples of the halogen ion source include an ammonium halide salt,preferably a tertiary or quaternary alkyl ammonium halide salt, and morepreferably a triethylamine hydrohalide salt or a di-1-propylethylaminehydrohalide salt.

In addition, examples of other halogen ion sources that are soluble inorganic solvents include a phosphonium halide salt, preferably an alkylphosphonium halide salt having an alkyl group of C₂ or more.

By making a halogen ion source which is soluble in an organic solvent tobe present in the reaction system, it is possible to suppress thegeneration of byproducts, and to increase the selectivity and yield forthe synthesis reaction of the compound represented by formula (4). Thehalogen ion source exhibits more significant effects when phosgene,diphosgene, triphosgene or phosphorus oxychloride is used as ahalogenating agent.

The used amount of the halogen ion source which is soluble in organicsolvents is not particularly limited, although it is preferably 0.8times or more the molar amount of the halogen atom, and more preferably1 to 6 times the molar amount of the halogen atom, relative to thecompound represented by formula (4).

(Organic Solvent)

In the production method of the present invention, it is possible to usean organic solvent. Usable organic solvents are not particularlylimited, although haloalkanes are preferred, and methylene chloride orchloroform is more preferred.

(Other Reaction Sub-Materials)

In the production method of the present invention, it is preferable thata deoxidizing agent be present, in addition to the halogen ion source.An amine soluble in organic solvents is desirable as the deoxidizingagent, and tertiary alkyl amines having an alkyl group of C₂ or more aremore preferred, and triethylamine or di-1-propylethyl amine isparticularly preferred.

The amount of the deoxidizing agent used is preferably at least anamount that may almost completely capture the hydrogen halide generatedas a result of the reaction, and more specifically, at least one timethe molar amount of hydrogen halide generated.

The upper limit of the amount used is preferably six times the molaramount of hydrogen halide generated. In the present invention, thecoexistence of a halogen ion source and a deoxidizing agent ispreferred.

(Reaction Between Compound Represented by Formula (4) and HalogenatingAgent)

The reaction between the compound represented by the formula (4) and thehalogenating agent is not particularly limited in terms of the techniqueemployed. For example, the reaction may be carried out by dissolving ahalogen ion source and a deoxidizing agent that are used as necessary inan organic solvent, adding the compound represented by formula (4) tothe solution, followed by the addition of a halogenating agent thereto.In the present invention, in order to achieve especially high yield, itis preferable to dissolve the halogen ion source and the deoxidizingagent that are used as necessary in an organic solvent, followed byadding the compound represented by formula (4) and the halogenatingagent almost simultaneously to the solution. The addition of thehalogenating agent may be carried out by dropwise addition of an organicsolvent solution of the halogenating agent or by blowing in a gaseoushalogenating agent. Moreover, addition of the compound represented byformula (4) may be carried out by the dropwise addition of the liquid.

The temperature from the start of the reaction until the end of thereaction is not particularly limited, although in view of enhancing theselectivity, the temperature is preferably not more than 40° C., andmore preferably within the range from −40° C. to 20° C.

By the production method of the present invention, it is possible toobtain a compound represented by formula (5). A, a¹, a², a³, a⁴, R¹, R²and in formula (5) are the same as defined above for A, a¹, a², a³, a⁴,R¹, R² and n in formula (4). X represents a halogen atom such as afluorine atom, a chlorine atom, a bromine atom or an iodine atom. Itshould be noted that in the cases where the compound represented byformula (4) serving as a raw material is a compound represented byformula (7), it is possible to obtain a compound represented by formula(8). In the formula (8), A, 1, R¹, R², R⁵ and R⁶ are the same as definedabove for A, 1, R¹, R², R⁵ and R⁶ in formula (7), and X represents ahalogen atom.

[3-2] Second Embodiment

The method for producing a nitrogen-containing heterocyclic compoundaccording to the present invention includes a step of converting acompound represented by formula (9) into a compound represented byformula (10), and a step of reacting the compound represented by theformula (10) with a halogenating agent to synthesize a compoundrepresented by formula (11).

The raw material used in the production method of the present inventionis a compound represented by formula (9). The compound corresponds to acompound represented by the formula (4) in which all of a¹, a², a³ anda⁴ represent carbon atoms and also at least one of A is a grouprepresented by formula (6a). It should be noted that * indicates abinding site in the formula (6a).

Specific examples of A, R¹ and R² in formula (9) include the same asthose described above as specific examples in the aforementionedformulae (4) and (5). In addition, k and m in formula (9), formula (10)and formula (11) are the same as defined above for k and m in theformula (1).

In the formula (9) or formula (6a), R⁶ represents an unsubstituted orsubstituted alkylcarbonyl group, an unsubstituted or substitutedarylcarbonyl group, an unsubstituted or substituted heteroarylcarbonylgroup, an unsubstituted or substituted alkoxycarbonyl group, anunsubstituted or substituted alkylsulfonyl group, or an unsubstituted orsubstituted arylsulfonyl group, and specific examples thereof includethe same as those described above as specific examples for R³ and R⁴. Ofthese, an unsubstituted or substituted alkylcarbonyl group, anunsubstituted or substituted arylcarbonyl group, an unsubstituted orsubstituted heteroarylcarbonyl group, or an unsubstituted or substitutedalkoxycarbonyl group is preferred, an unsubstituted or substitutedalkoxycarbonyl group is more preferred, and an unsubstituted orsubstituted C₃₋₈ alkoxycarbonyl group is particularly preferred.

The compounds represented by formula (9) (except for 2-ethoxycarbonylamino-6-methylpyridine-N-oxide) are novel substances. The compound maybe obtained by a method in which the corresponding 2-picoline derivativeis oxidized with meta-chloroperbenzoic acid, a method in which thecorresponding 2-picoline derivative is oxidized with hydrogen peroxidein the presence of tungstic acid (refer to U.S. Pat. No. 3,047,579), orthe like.

(Step of Converting Compound Represented by Formula (9) into CompoundRepresented by Formula (10))

Examples of the method to convert a compound represented by formula (9)into a compound represented by formula (10) include a method in which acompound represented by R²X¹ is reacted with the compound represented byformula (9). Here, R² is the same as R² in the formula (10) describedlater, and X¹ represents a chlorine atom or a bromine atom.

By going through the conversion step, it is possible to obtain acompound represented by formula (10).

A, k, R¹, R², R⁶ and m in formula (10) are the same as defined above forA, k, R¹, R², R⁶ and m in formula (9).

In the formula (10), R² represents an unsubstituted or substitutedalkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group,an unsubstituted or substituted heteroarylcarbonyl group, anunsubstituted or substituted alkoxycarbonyl group, an unsubstituted orsubstituted alkylsulfonyl group, or an unsubstituted or substitutedarylsulfonyl group, and specific examples thereof include the same asthose described above as specific examples for R³ and R⁴. When m is 2 ormore, each R² may be the same or may be different from each other.

(Reaction Between Compound Represented by Formula (10) and HalogenatingAgent)

For the reaction between a compound represented by formula (10) and a 20halogenating agent, the same technique as that used in the reactionbetween a compound represented by formula (4) and a halogenating agentin the first embodiment may be employed. In addition, examples of thehalogenating agents, halogen ion sources, organic solvents and otherreaction auxiliary materials that may be used in the second embodimentinclude the same as those that may be used in the first embodiment.

By the production method according to the second embodiment of thepresent invention, it is possible to obtain a compound represented byformula (11).

In the formula (11), A, k, R¹, R², R⁶, R² and m are the same as definedabove for A, k, R¹, R², R⁶, R² and m in the aforementioned formula (9)and formula (10).

In the formula (11), X represents a halogen atom such as a fluorineatom, a chlorine atom, a bromine atom or an iodine atom.

[3-3] Third Embodiment

The method for producing a nitrogen-containing heterocyclic compoundaccording to the present invention includes a step of reacting thecompound represented by formula (9) with a halogenating agent in thepresence of a compound represented by formula (12) to synthesize acompound represented by formula (13).

For the method for reacting the compound represented by formula (9) witha halogenating agent in the presence of a compound represented byformula (12), the same technique as that used in the method to react thecompound represented by formula (4) with a halogenating agent in thefirst embodiment may be employed, with the exception that the compoundrepresented by formula (12) is present in the reaction system. Inaddition, examples of the halogenating agents, halogen ion sources,organic solvents and other reaction auxiliary materials that may be usedin the third embodiment include the same as those that may be used inthe first embodiment.

By the production method according to the third embodiment of thepresent invention, it is possible to obtain a compound represented byformula (13).

In the formula (12), R⁸ represents an unsubstituted or substitutedalkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group,or an unsubstituted or substituted alkoxycarbonyl group, and specificexamples thereof include the same as those described above as specificexamples for R³. In addition, X¹ in the formula (12) represents achlorine atom or a bromine atom.

In the formula (13), specific examples of A, R¹, R², R⁶ and R⁸ includethe same as those described above as specific examples for A, R¹, R², R⁶and R⁸ in the aforementioned formula (9) and formula (12). In theformula (13), k and m are the same as defined above for k and m in theaforementioned formula (9) and formula (12). In addition, X in theformula (13) represents a halogen atom such as a fluorine atom, achlorine atom, a bromine atom or an iodine atom.

The compounds represented by the formula (5), (8), (11) or (13) that areobtained by the production method of the present invention are useful asintermediates for the synthesis of agricultural chemicals,pharmaceutical products, or the like.

EXAMPLES

The present invention will be described in more detail below using aseries of examples and comparative examples. However, the technicalscope of the present invention is in no way limited by these examples.

Example A1

1.65 g (5 mmol) of sodium tungstate (VI) dihydrate (Na₂WO₄.2H₂O) wasdissolved in 20 ml of distilled water. 6 ml of 10% phosphoric acid(H₃PO₄) was added to the obtained solution, and concentrated sulfuricacid was then added thereto to adjust the pH to 2.0.

8 ml of a 25% aqueous hydrogen peroxide solution was added to thesolution, and the resulting mixture was stirred at room temperature for20 minutes. An aqueous solution of tetra(n-butyl) ammonium chloride (4mol) was slowly added dropwise to the reaction mixture which had beenstirred vigorously. After the completion of the dropwise addition, theresulting mixture was stirred at room temperature for 50 minutes.

The obtained reaction solution was filtered, and the residue was washedwith water. The obtained residue was dissolved in chloroform and wasthen dehydrated and dried with anhydrous sodium sulfate, and theobtained solution was filtered. Then, the solvent was removed from thefiltrate by distillation, thereby yielding colorless crystals([(n-C₄H₉)₄N]₃ [PW₄O₂₄]).

0.567 g of a 30% aqueous hydrogen peroxide solution was charged into areaction vessel. 0.093 g of the tungstophosphoric acid salt obtainedabove was added thereto.

Subsequently, 1.25 ml of a methylene chloride solution of2-[(t-butoxycarbonyl)amino]-6-methylpyridine having a concentration of 2mol/L was added thereto, and the resulting mixture was stirred at roomtemperature for 20 minutes. Then, the mixture was stirred for 1 hourwhile refluxing.

2 ml of water and 3 ml of methylene chloride were added to the reactionsolution, followed by extraction and liquid separation. The resultingaqueous layer was extracted twice with 3 ml of methylene chloride, andall of the obtained organic layers were brought together. The resultingorganic layer was analyzed by HPLC. As a result, it was shown that2-[(t-butoxycarbonyl)amino]-6-methylpyridine-N-oxide was obtained with ayield of 97.6%.

The measurement results of ¹H-NMR spectrum of the obtained2-[(t-Substitute Specificationbutoxycarbonyl)amino]-6-methylpyridine-N-oxide were as follows.

¹H-NMR (CDCl₃, δ ppm): 1.53 (9H, s), 2.55 (3H, s), 6.87 (1H, d, J=7.6Hz), 7.19 (1H, t, J=8.2 Hz), 8.01 (1H, d, J=8.8 Hz), 9.43 (1H, brs).

Example A2

0.2 g of a 10% aqueous phosphoric acid solution (H₃PO₄) was added to areaction vessel charged with 0.041 g of sodium tungstate (VI) dihydrate(Na₂WO₄.2H₂O), and 0.567 g of a 30% aqueous hydrogen peroxide solutionwas then added thereto.

Subsequently, 0.031 g of benzyltri(n-butyl)ammonium chloride was addedthereto, and the resulting mixture was stirred at room temperature for10 minutes. White crystals precipitated in the reaction solution.

Subsequently, 1.25 ml of a methylene chloride solution of2-[(t-butoxycarbonyl)amino]-6-methylpyridine having a concentration of 2mol/l was added thereto, and the resulting mixture was stirred at roomtemperature for 5 minutes. Then, the mixture was stirred for 2 hourswhile refluxing.

5 ml of water was added to the obtained reaction solution for extractionand liquid separation, and the resulting aqueous layer was extractedtwice with 3 ml of methylene chloride. All of the obtained organiclayers were brought together. The resulting organic layer was analyzedby HPLC. As a result, it was shown that2-[(t-butoxycarbonyl)amino]-6-methylpyridine-N-oxide was obtained with ayield of 97.1%.

Example A3

1.63 g of a 10% aqueous phosphoric acid solution (H₃PO₄) was added to areaction vessel charged with 0.274 g of sodium tungstate (VI) dihydrate(Na₂WO₄.2H₂O), and 2.45 g of a 30% aqueous hydrogen peroxide solutionwas then added thereto.

Subsequently, 0.207 g of benzyltri(n-butyl)ammonium chloride was addedthereto, and the resulting mixture was stirred at room temperature for10 minutes. White crystals precipitated in the reaction solution.

Subsequently, 8.3 ml of a chloroform solution of2-[(t-butoxycarbonyl)amino]-6-methylpyridine having a concentration of 2mol/l was added thereto, and the resulting mixture was stirred at roomtemperature for 5 minutes. Then, the mixture was stirred for 2 hourswhile refluxing.

10 ml of water was added to the obtained reaction solution forextraction and liquid separation, and the resulting aqueous layer wasextracted twice with 5 ml of chloroform. All of the obtained organiclayers were brought together. The resulting organic layer was analyzedby HPLC. As a result, it was shown that2-[(t-butoxycarbonyl)amino]-6-methylpyridine-N-oxide was obtained with ayield of almost 100%.

From the results shown above, it is clear that a substitutedamino-6-methylpyridine-N-oxide derivative can be obtained with highselectivity by oxidizing a substituted amino-6-methylpyridine derivativeusing a peroxide, such as hydrogen peroxide, in the presence of atungstophosphoric acid salt, such as [(n-C₄H₉)₄N]₃[PW₄O₂₄] or[(C₆H₅CH₂)(n-C₄H₉)₃N]₃[PW₄O₂₄]. In addition, from a comparison betweenExample A1 and Example A2, it is apparent that the selectivity of theoxidation reaction of a substituted amino-6-methylpyridine derivativedoes not decline, even when a tungstophosphoric acid salt is used as itis in the oxidation reaction without isolation after the preparationthereof. From a comparison between Example A2 and Example A3, it isevident that a target product can be obtained with a high yield with asmaller amount of catalyst and oxidizing agent when chloroform is usedas a reaction solvent.

Example B1

7 ml of a methylene chloride solution containing 0.54 g (2 4 mmol) of2-t-butoxycarbonyl amino-6-methylpyridine-N-oxide was cooled to −17° C.0.63 g (5.3 mmol) of thionyl chloride was added thereto, and 3 ml of amethylene chloride solution containing 1.02 g (8.6 mmol) oftriethylamine was then added dropwise thereto. The reaction was allowedto proceed for 3 hours at −15° C. Then, 20 ml of water was added theretoat −10° C. Then, the pH was adjusted to 11 with caustic soda.2-t-butoxycarbonyl amino-6-chloromethylpyridine which was the targetproduct was obtained with a yield of 60% in the organic layer obtainedby liquid separation.

Example B2

A solution A was prepared by dissolving 1.35 g (6.0 mmol) of2-t-butoxycarbonyl amino-6-methylpyridine-N-oxide in 18 ml of methylenechloride and was cooled to −15° C.

A solution B was prepared by dissolving 1.57 g (13.2 mmol) of thionylchloride in 18 ml of methylene chloride.

A solution C was prepared by dissolving 2.43 g (24.0 mmol) oftriethylamine in 18 ml of methylene chloride.

The solution B was added dropwise to the solution A. When 5 minutes hadelapsed from the start of the dropwise addition, the dropwise additionof solution C was started. The solution B was added dropwise over 70minutes and the solution C was added dropwise over 105 minutes, so thateach of the solutions was added entirely. When one hour had elapsedafter the completion of the dropwise addition, 100 ml of water was addedthereto. Then, the pH was adjusted to 3.7 by adding saturated sodiumbicarbonate water thereto. 2-t-butoxycarbonylamino-6-chloromethylpyridine which was the target product was obtainedwith a yield of 62% in the organic layer obtained by liquid separation.

Example B3

0.3 g (3.0 mmol) of triethylamine and 2.48 g (18.0 mmol) oftriethylamine hydrochloride were dissolved in 18 ml of methylenechloride. The solution was cooled to −14° C., and 18 ml of a methylenechloride solution containing 1.34 g (6.0 mmol) of 2-t-butoxycarbonylamino-6-methylpyridine-N-oxide and 2.13 g (21.1 mmol) of triethylamineand 18 ml of a methylene chloride solution containing 1.57 g (13.2 mmol)of thionyl chloride were added dropwise at the same time. The reactionwas allowed to proceed for 2 hours at −15° C. Then, 15 ml of water wasadded thereto. Then, the pH was adjusted to 13 with caustic soda. Afterliquid separation, the organic layer was washed with dilute hydrochloricacid. 2-t-butoxycarbonyl amino-6-chloromethyl pyridine which was thetarget product was obtained with a yield of 55% in the resulting organiclayer.

Example B4

0.31 g (3.1 mmol) of triethylamine and 2.57 g (18.7 mmol) oftriethylamine hydrochloride were dissolved in 18 ml of chloroform. Thesolution was cooled to −14° C., and 18 ml of a chloroform solutioncontaining 1.34 g (6.0 mmol) of 2-t-butoxycarbonylamino-6-methylpyridine-N-oxide and 2.20 g (21.8 mmol) of triethylamineand 18 ml of a methylene chloride solution containing 1.63 g (13.7 mmol)of thionyl chloride were added dropwise at the same time over 105minutes. The reaction was allowed to proceed for 2 hours at −15° C.Then, 30 ml of water was added thereto. Then, the pH was adjusted to 5with saturated sodium bicarbonate water. 2-t-butoxycarbonylamino-6-chloromethylpyridine which was the target product was obtainedwith a yield of 77% in the organic layer obtained by liquid separation.

Example B5

0.224 g (1.0 mmol) of 2-t-butoxycarbonylamino-6-chloromethylpyridine-N-oxide was dissolved in 2 ml ofchloroform. While ice-cooling the resultant with stirring, 0.139 ml (1.0mmol) of triethylamine, 0.174 ml (1.5 mmol) of benzoyl chloride, 0.088ml (1.2 mmol) of thionyl chloride and 0.14 g (1.0 mmol) of triethylaminehydrochloride were sequentially added thereto. After completion of theaddition, 0.418 ml (3.0 mmol) of triethylamine which was dissolved in 2ml of chloroform was added dropwise over 15 minutes. After thecompletion of the dropwise addition, the resulting mixture was stirredunder ice cooling for 5 minutes, and then at room temperature for 30minutes. Then, the resultant was quantitatively analyzed by HPLC.2-benzoyl-t-butoxycarbonyl amino-6-chloromethylpyridine which was thetarget product was obtained with a yield of 72%.

Example B6

1 ml of a chloroform solution containing 0.22 g (1.0 mmol) of2-t-butoxycarbonyl amino-6-methylpyridine-N-oxide was added dropwise to5 mL of a chloroform solution containing 2.0 mmol of para-nitrobenzoylchloride over 10 minutes at room temperature. After 20 minutes hadelapsed therefrom, the reaction mixture was cooled to −15° C., and 0.30g (3.0 mmol) of triethylamine was added dropwise thereto over 5 minutes.After 5 minutes had elapsed therefrom, 1 ml of a chloroform solutioncontaining 0.20 g (0.67 mmol) of triphosgene was added dropwise theretoover a period of 5 minutes. After 20 minutes had elapsed therefrom, 0.20g (2.0 mmol) of triethylamine was added dropwise thereto over 5 minutes,and the resulting mixture was then stirred for 30 minutes. The resultingreaction solution was poured into saturated sodium bicarbonate water,and was extracted with ethyl acetate. The organic layer was dried withmagnesium sulfate, filtered and concentrated. The resulting crudeproduct was purified by column chromatography (hexane/ethyl acetate) toobtain 2-t-butoxycarbonyl-2-para-nitrobenzoylamino-6-chloromethylpyridine which was the target product with a yieldof 64% (as measured by HPLC).

Example B7

A solution C was obtained by dissolving 0.27 g (2.5 mmol) oftriethylamine and 2.07 g (15 mmol) of triethylamine hydrochloride in 15mL of chloroform.

A solution A was prepared by adding chloroform to 1.14 g (5.07 mmol) of2-t-butoxycarbonyl amino-6-chloromethylpyridine-N-oxide and 1.77 g (17.5mmol) of triethylamine up to a total volume of 10 mL.

1.16 g (11.77 mmol) of phosgene was dissolved in chloroform and broughtup to a total volume of 10 mL, thereby preparing a solution B.

The solution C was cooled to around −15° C. The solution A and solutionB were added dropwise thereto at the same time over 40 minutes. Afterthe completion of the dropwise addition, the reaction mixture wasstirred for 30 minutes at −15° C. 10 mL of water was added to theaforementioned reaction mixture maintained at 0° C. or below. The pH wasadjusted to 11 or more by adding an aqueous solution of caustic sodahaving a concentration of 28%. Following liquid separation, theresulting aqueous layer was extracted with chloroform. When the organiclayer was quantitatively analyzed by HPLC, it was shown that2-t-butoxycarbonyl amino-6-chloromethylpyridine which was the targetproduct was obtained with a yield of 69%. 1% of byproducts (in terms ofHPLC relative area percentage) was included therein.

Example B8

The reaction was carried out in the same manner as in Example B7 withthe exception that triethylamine was replaced with di-1-propyl ethylamine and triethylamine hydrochloride was replaced with di-1-propylethyl amine hydrochloride, respectively. The organic layer obtained bychloroform extraction was analyzed by HPLC. As a result, the byproductcontent was 1% (HPLC relative area percentage). The organic layer wasconcentrated, and the resulting crude product was purified by silica gelcolumn chromatography (hexane/ethyl acetate) to obtain 0.67 g of2-t-butoxycarbonyl amino-6-chloromethylpyridine (yield: 55%) which wasthe target product.

Example B9

20.37 g (92.2 mmol) of 2-t-butoxycarbonyl amino-6-methylpyridine wasdissolved in 100 mL of chloroform, and the resulting solution was cooledwith ice water. 25 g (101.4 mmol) of a 70% by weight product ofmeta-chloroperbenzoic acid was added thereto. After confirming thatthere is no large heat generation, the temperature was raised to roomtemperature. After 2 hours had elapsed, 20 mL of water was addedthereto. Then, the pH was adjusted to 14 by adding an aqueous solutionof caustic soda having a concentration of 28%. Following liquidseparation, the resulting aqueous layer was extracted with chloroform.The chloroform layer was washed with a 28% aqueous solution of causticsoda and then with water, and then dried with magnesium sulfate.Chloroform was removed by distillation under reduced pressure to obtain21.30 g of 2-t-butoxycarbonyl amino-6-methylpyridine-N-oxide (yield:99.6%) in a light orange oily form.

The NMR spectrum and MS spectrum of the obtained 2-t-butoxycarbonylamino-6-methylpyridine-N-oxide were measured, and the following resultswere obtained.

¹H NMR: 1.53 (9H, s), 2.55 (3H, s), 6.87 (1H, d, J=7.6 Hz), 7.19 (1H, t,J=8.2 Hz), 8.01 (1H, d, J=8.8 Hz), 9.43 (1H, brs).

¹³C NMR: 18.09, 28.01, 81.76, 110.23, 117.65, 126.68, 144.31, 146.85,151.37.

MS m/z: 224 (M⁺), 168, 151, 124, 107.

Example B10

4 mL of a chloroform solution containing 0.45 g (2 mmol) of2-t-butoxycarbonyl amino-6-methylpyridine-N-oxide and 0.26 g (2 mmol) ofdiisopropylethylamine was prepared, and was adjusted to 10° C. 0.29 g (2mmol) of benzoyl chloride was added dropwise to the solution over 10minutes at 10° C. After stirring further for 40 minutes at 10° C., 5 mLof water was added thereto, followed by liquid separation. Thechloroform layer obtained by liquid separation was washed twice with 5mL of water, and then dried with magnesium sulfate, followed byfiltration. The resulting solution was concentrated under reducedpressure and dried to obtain 0.64 g of 2-t-butoxycarbonyl-2-benzoylamino-6-methylpyridine-N-oxide (yield: 97%) in the form of yellow-brownamorphous which was the target product.

The NMR spectrum of the obtained 2-t-butoxycarbonyl-2-benzoylamino-6-methylpyridine-N-oxide was measured, and the following resultswere obtained.

¹H-NMR: 1.23 (9H, s), 2.54 (3H, s), 7.20 (d, J=7.6 Hz, 1H), 7.23 (d,J=5.4 Hz, 1H), 7.35 (dd, J=7.6, 2.4 Hz, 1H), 7.44 (t, J=7.4 Hz, 2H),7.53 (tt, J=7.4, 1.2 Hz, 1H), 7.92 (dd, J=6.8, 1.2 Hz, 2H).

¹³C-NMR: 18.2, 27.5, 84.3, 123.4, 124.5, 124.8, 128.0, 128.7, 131.9,135.6, 144.7, 149.2, 151.0, 170.9.

Example B11

2 mL of a chloroform solution containing 0.24 g (1 mmol) of2-t-butoxycarbonyl amino-6-methylpyridine and 0.26 g (2 mmol) ofdiisopropylethylamine was prepared, and was cooled in ice water. Theabove mixed solution was added dropwise at 0° C. to 0.3 mL of achloroform solution containing 0.11 g (1.2 mmol) of methylchloroformate. After stirring further for 20 minutes, the temperaturewas raised to room temperature. After stirring further for 5 hours atroom temperature, 5 mL of water and 1 mL of 3N hydrochloric acid wereadded thereto, followed by liquid separation. The organic layer obtainedby liquid separation was dried with magnesium sulfate, followed byfiltration, and the resulting solution was concentrated under reducedpressure to obtain 0.27 g of 2-t-butoxycarbonyl-methoxycarbonylamino-6-methyl pyridine-N-oxide (yield: 96%) as a pale yellow oilyliquid which was the target product.

The NMR spectrum of the obtained 2-t-butoxycarbonyl-methoxycarbonylamino-6-methylpyridine-N-oxide was measured, and the following resultswere obtained.

¹H-NMR: 1.44 (9H, s), 2.54 (3H, s), 3.79 (3H, s), 7.13-7.26 (m, 3H).

Comparative Example B1

10 ml of a methylene chloride solution containing 1.99 g (6.7 mmol) oftriphosgene was cooled to 0° C. 5 ml of a methylene chloride solutioncontaining 1.12 g (5 mmol) of 2-t-butoxycarbonylamino-6-methylpyridine-N-oxide and 5 ml of a methylene chloride solutioncontaining 1.01 g (10 mmol) of di-1-propylamine were each added dropwisethereto at the same time. After the completion of the dropwise addition,the liquid temperature was adjusted to room temperature, and theresulting mixture was then stirred for 1 hour. The reaction solution waspoured into saturated sodium bicarbonate water, and was then extractedwith methylene chloride. The organic layer was dried with magnesiumsulfate, filtered and concentrated. The resulting crude product waspurified by column chromatography (hexane/ethyl acetate). Only 73 mg of2-t-butoxycarbonyl amino-6-chloromethylpyridine which was the targetproduct was obtained (yield: 3%). On the other hand, 503 mg (67%) ofbyproducts in the form of a white solid were produced.

Comparative Example B2

1.03 g (8 mmol) of di-1-propylethyl amine and 0.67 g (3 mmol) of2-t-butoxycarbonyl amino-6-methylpyridine-N-oxide were dissolved in 10ml of methylene chloride, and the resulting solution was then cooled to−15° C. 20 mL of a methylene chloride solution containing 0.60 g (2mmol) of triphosgene was added dropwise thereto over a period of 2 hourswhile maintaining the inner temperature at −15° C. After the completionof the dropwise addition, the resulting liquid was stirred for 1 hour at−15° C. 20 mL of water was added to the aforementioned reaction mixturemaintained at 0° C. or below. The pH was adjusted to 11 or more byadding an aqueous solution of caustic soda having a concentration of28%. Following liquid separation, the resulting aqueous layer wasextracted with ethyl acetate. The organic layer was washed with water,dried with anhydrous magnesium sulfate, and then concentrated underreduced pressure. The resulting crude product was purified by silica gelcolumn chromatography (hexane/ethyl acetate). 0.18 g of2-t-butoxycarbonyl amino-6-chloromethylpyridine which was the targetproduct was obtained (yield: 25%). 4% of byproducts (in terms of HPLCrelative area percentage) was produced.

Comparative Example B3

The reaction was carried out in the same manner as in Example B8 withthe exception that no di-1-propyl ethyl amine hydrochloride was added.The yield of 2-t-butoxycarbonyl amino-6-chloromethylpyridine afterpurification by silica gel column chromatography was 32%. 13% ofbyproducts (in terms of HPLC relative area percentage) was produced.

INDUSTRIAL APPLICABILITY

According to the production method of the present invention,nitrogen-containing heterocyclic compounds such as a substitutedamino-6-methylpyridine-N-oxide derivative, and a haloalkyl,nitrogen-containing heterocyclic derivative can be obtained with highselectivity and also in high yield. The nitrogen-containing heterocycliccompound obtained by the production method of the present invention isuseful as an intermediate for the industrial production of agriculturalchemicals or the like.

The invention claimed is:
 1. A method for producing a compound represented by formula (13) comprising reacting a compound represented by formula (9) with a halogenating agent in a presence of a compound represented by formula (12),

wherein each of R¹ and R² independently represents a hydrogen atom, or an unsubstituted or substituted alkyl group, and R¹ and R² may form a ring together, R⁶ represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, an unsubstituted or substituted heteroarylcarbonyl group, an unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted alkylsulfonyl group, or an unsubstituted or substituted arylsulfonyl group, R⁸ represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted alkoxycarbonyl group, A represents a hydroxyl group, a thiol group, an amino group, a nitro group, a halogen atom or an organic group, m represents any one of integers of 1 to 4, k represents any one of integers of 0 to 3, wherein k +m 4, X represents a halogen atom, and X¹ represents a chlorine atom or a bromine atom.
 2. The method according to claim 1, wherein the reaction is carried out in a presence of a halogen ion source that is soluble in an organic solvent.
 3. The method according to claim 2, wherein the halogen ion source that is soluble in an organic solvent is a halogenated ammonium salt or a halogenated phosphonium salt.
 4. The method according to claim 2, wherein the halogen ion source that is soluble in an organic solvent is a tertiary or quaternary alkyl ammonium halide salt having an alkyl group of C₂ or more, or an alkyl phosphonium halide salt having an alkyl group of C₂ or more.
 5. The method according to claim 1, wherein the halogenating agent is at least one selected from the group consisting of thionyl chloride, thionyl bromide, phosphorus oxychloride, sulfuryl chloride, phosgene, diphosgene and triphosgene.
 6. The production method according to claim 2, wherein the halogenating agent is at least one selected from the group consisting of thionyl chloride, thionyl bromide, phosphorus oxychloride, sulfuryl chloride, phosgene, diphosgene and triphosgene.
 7. The production method according to claim 3, wherein the halogenating agent is at least one selected from the group consisting of thionyl chloride, thionyl bromide, phosphorus oxychloride, sulfuryl chloride, phosgene, diphosgene and triphosgene.
 8. The production method according to claim 4, wherein the halogenating agent is at least one selected from the group consisting of thionyl chloride, thionyl bromide, phosphorus oxychloride, sulfuryl chloride, phosgene, diphosgene and triphosgene. 